|Year : 2021 | Volume
| Issue : 2 | Page : 278-284
Secretory carcinoma of salivary gland origin: A recently established masquerader
Shilpi Budhiraja1, Rajeev Kumar1, Gaurav Khanna2, Prem Sagar1, Sudhir Arava2, Adarsh Barwad2, Asit Ranjan Mridha2
1 Department of Otolaryngology and Head Neck Surgery, All India Institute of Medical Sciences, New Delhi, India
2 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||02-Apr-2020|
|Date of Decision||10-Apr-2020|
|Date of Acceptance||12-Jul-2020|
|Date of Web Publication||11-May-2021|
Department of Otolaryngology and Head Neck Surgery, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
Secretory carcinoma (SC) of the salivary gland is considered to be a low-intermediate grade tumor with the potential of locally aggressive behavior. This tumor is similar both genetically (ETV6-NTRK3 fusion) and histologically to secretory carcinoma of the breast. We intent to share our experience of four cases of SC in terms of clinical behavior, pathological features, and treatment outcome. Medical records of four cases of SC were retrieved and analyzed for clinical presentation, surgical treatment, and outcome. Pathological data was reanalyzed along with immunohistochemistry. Out of the four identified SC cases, three were men. Two lesions originated from the parotid gland and two from minor salivary glands. Two of these cases exhibited features of locally aggressive pattern. SC of salivary gland origin has distinct histological and immunohistochemical features apart from the characteristic genetic translocation and fusion. Surgery with or without adjuvant radiotherapy is the treatment of choice. To establish the biological behavior of this tumor, larger case series with long-term follow-up is desirable.
Keywords: Acinar cell carcinoma, mammary analogue secretory carcinoma, salivary gland neoplasms
|How to cite this article:|
Budhiraja S, Kumar R, Khanna G, Sagar P, Arava S, Barwad A, Mridha AR. Secretory carcinoma of salivary gland origin: A recently established masquerader. Indian J Cancer 2021;58:278-84
|How to cite this URL:|
Budhiraja S, Kumar R, Khanna G, Sagar P, Arava S, Barwad A, Mridha AR. Secretory carcinoma of salivary gland origin: A recently established masquerader. Indian J Cancer [serial online] 2021 [cited 2021 Jun 15];58:278-84. Available from: https://www.indianjcancer.com/text.asp?2021/58/2/278/315804
| » Introduction|| |
Secretory carcinoma (SC) is a recently described entity. It is characterized by recurrent balanced chromosomal translocation t(12;15)(p13;q25) which was first detected in infantile fibrosarcoma and congenital mesoblastic nephroma. SC owes its name to secretory carcinoma of the breast, which is a rare malignancy seen in adolescent girls, based on histological, immunohistochemical (IHC), and genetical similarity., Before Skalova's description, this entity was confused with various other low-grade salivary gland tumors like adenocarcinoma (NOS), mucin-producing signet ring adenocarcinoma, mucoepidermoid carcinoma, and acinic cell carcinoma (ACC).,, SC has been most falsely reported as ACC in the majority of cases., Though chromosomal translocation causing ETV6 and NTRK3 gene fusion is characteristic, some authors have supported the use of morphological features and IHC as a very useful tool for the diagnosis.,, This grossly circumscribed and unencapsulated tumor is considered to be a slow-growing low-grade malignant tumor with occasional reports of surrounding tissue infiltration. Cases of aggressive behavior with a rapid increase in size as well as regional and distant metastasis have also been reported in the literature., SC is most commonly seen in the parotid gland, other unusual sites being lip, soft palate, buccal mucosa, and submandibular gland in decreasing order of incidence.
We present a case series of four patients in terms of their clinical presentation, pathological profile, treatment, and outcome on long-term follow-up. The existing literature is mainly focussed on the pathological description of SC. Our series will add to the clinical presentation and treatment outcome aspects of SC which would help formulate the management protocol and prognostication of this new entity.
| » Materials and Methods|| |
A retrospective review of four cases of SC treated between 20014–18 in a tertiary care hospital was performed. Patients' demographic profile, clinical presentation, radiological findings, intraoperative details, and treatment outcome were noted. The pathological data was reviewed and immunohistochemistry was also reanalyzed.
| » Results|| |
In these four cases of SC, the mean age was 24.7 years (age range 15–50 years), and there was a preponderance among males (M: F =3:1). The duration of symptoms was between 6 months to 8 years. All the males were in the young age group (15–22 years), and their disease symptoms were for 2–8 years before they presented to us. Two of these young patients had features suggestive of aggressive disease. The detailed demographic profile and clinical features of all the cases are summarized in [Table 1]. Radiological pictures of only two patients could be retrieved [Figure 1]a, [Figure 1]b, [Figure 1]c showing the location and extent of the lesions, respectively. The preoperative diagnosis for all the four patients was based on fine-needle aspiration cytology (FNAC)/biopsy; while the final histopathological diagnosis is summarized in [Table 2].
|Figure 1: Contrast-enhanced computed tomography of the face shows a hyperintense lesion in the left side palate (a, case 1) and an enhancing lesion in the left buccal space (b and c for case 4)|
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All patients underwent surgery with curative intent. Case 1 presented with a palatal mass that was managed by wide local excision and local buccal mucosa rotation flap for reconstruction of the palatal defect. Case 2 and 3 presented with slow-growing parotid swelling with overlying normal skin. Case 2 had a history of tumor excision and progressive facial weakness after excision. As the tumor was involving facial nerve intraoperatively, a radical parotidectomy was performed. In case 3, deep lobe was not involved clinically and radiologically, hence superficial parotidectomy was done. Prophylactic lymph node dissection was not planned in any of the above two cases as preoperative FNAC was suggestive of pleomorphic adenoma. Case 4 presented with buccal mucosa mass with skin infiltration with a history of excision biopsy thrice (at other hospitals) in the past with no definitive diagnosis on histopathology. He underwent wide local excision with pectoralis major myocutaneous flap for reconstruction along with extended supraomohyoid neck dissection due to aggressive behavior of the tumor. He received adjuvant radiotherapy in view of skin infiltration and multiple recurrences. The surgical details, intraoperative findings including pointers for local aggression, and long-term follow-up, along with the outcome for all the four cases are summarized in [Table 2].
The histological results for each case with salient features are summarized in [Table 3]. The genetic analysis was not done in any case due to the unavailability of the facility in our institute. In case 1, on gross examination, a well-circumscribed tumor measuring 1.7 × 1.5 × 1.1 cm was identified with overlying ulcerated mucosa. It was involving the left side of the soft palate. Cut surface revealed a circumscribed gray-white-to-tan colored lesion with microcystic areas in the periphery. Areas of hemorrhage and necrosis were not seen grossly. On hematoxylin and eosin staining (H and E), tumor cells were arranged in sheets and prominent lobular architecture with pushing margins at the periphery. The tumor lobules were separated by fibrous septa, which were focally infiltrated by lymphocytes. The formation of microcysts at places with extracellular secretory material within their lumen was noted as seen in [Figure 2]a. On higher-magnification, the tumor cells were having a moderate amount of vacuolated and eosinophilic cytoplasm with nuclei showing moderate nuclear pleomorphism, vesicular chromatin, and inconspicuous nucleoli [Figure 2]b, [Figure 2]c, [Figure 2]d. Special stain for mucin did not reveal any zymogen granules. Perineural infiltration and lymphovascular embolization were not identified. On IHC, the tumor cells showed strong and diffuse immunopositivity for S100, vimentin, and cytokeratin 7.
|Figure 2: Case 1- (a) Low power picture of the case showing the circumscribed tumor. (H and E 40×) (b) Higher magnification showing characteristic papillary, cystic, and microcystic pattern of arrangement. (H and E 100×) (c and d) Microcysts with extracellular secretory material within lumina (c) and on further high power magnification, tumor cells with a moderate amount of vacuolated and eosinophilic cytoplasm with nuclei showing moderate nuclear pleomorphism, vesicular chromatin, and conspicuous nucleoli. Few cells are also showing intracytoplasmic secretions (d). (c-H and E 200×; d-H and E 400×)|
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Gross examination in case 2 showed a gray-white tumor from the right parotid region measuring 2 × 2 × 1.8 cm with clear surgical resection margins. H and E stained sections showed microcystic areas and cribriform islands with intervening thick septa which were infiltrated by lymphocytes. The tumor cells were cuboidal to polygonal with eosinophilic granular and multivacuolated cytoplasm. The nuclei were oval with granular chromatin and distinct nucleoli. On IHC, cells were strongly positive for cytokeratin 7, vimentin, diffuse nuclear, and cytoplasmic positive for S100 [Figure 3]a, [Figure 3]b, [Figure 3]c and Ki-67 labeling index was 10%. Gross cystic disease fluid protein (GCDFP) marker was also performed but results were positive [Figure 3]d
|Figure 3: Case 2- Immunohistochemistry: CK7, S100, Vimentin, and GCDFP marker positivity in figure 3a, b, c, and d respectively. Fig. 3d shows microcystic areas with intervening thick septa infiltrated by lymphocytes. The tumor cells are cuboidal to polygonal with eosinophilic granular and multivacuolated cytoplasm|
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In case 3, a well-circumscribed tumor from the left parotid region measuring 3 × 2 cm was seen with gray-to-tan cut surface on grossing. H and E stained sections showed cuboidal tumor cells forming microcystic areas containing eosinophilic material which was periodic-acid-Schiff (PAS) positive. On IHC, tumor cells were positive for cytokeratin (CK), S100, and vimentin, while negative for DOG1, progesterone, carcinoembryonic antigen (CEA), and CD34. In case 4, a well-circumscribed tumor measuring 2.4 × 2 × 1.6 cm with cut surface solid gray-brown was seen. On H and E stained sections, the tumor showed cells arranged in lobules and sheets with a few intervening microsysts which were filled bubbly eosinophilic secretions. The tumor cells showed mild-to-moderate nuclear pleomorphism with homogenous chromatin and a moderate amount of eosinophilic cytoplasm. No zymogen granules or basophilia noted in the cytoplasm were seen. On IHC, tumor cells were immunopositive for CK 7, vimentin, S100 (diffuse nuclear and cytoplasmic), and GCDFP.
| » Discussion|| |
SC is a recently described pathology that was newly incorporated into a long list of salivary gland tumors by World Health Organization. It was first described by Skalova in 2010 in a series of 16 cases with characteristic histopathological and IHC features, which was similar to rare juvenile breast cancer, SC. SC was first described by Divitt and Stewart., It occurs in adolescent girls and rarely in old age with no sex predilection., Histologically, these are well-circumscribed tumors with solid, tubular, and acinar growth patterns and with bland, pale nuclei. Recently it was established that SC harbors a balanced chromosomal translocation t(12;15)(p13; q25) which leads to a fusion between the ETV6 gene on chromosome 12 and NTRK3 gene on chromosome 15. It results in a constitutively active chimeric tyrosine kinase and probable activation of RAS-MAP kinase mitogenic and phosphatidyl inositol-3-kinase-AKT pathway.,,
Skalova was first to establish the similarities between a salivary gland tumor and SC of the breast, on histomorphological, IHC, and genetic grounds, and coined the term “Mammary Analogue of Secretory carcinoma”. It was also noted that most of the unusual variants of ACC from the extra-parotid origin and cystadenocarcinoma NOS reported in the past showed morphological features similar to SC and were later entitled as SC., Attributing to the similar tubulo-acinar architecture in salivary glands and breast tissue, multiple salivary gland lesions and tumors have been described to have their counterparts in the breast. The list includes pleomorphic adenoma, adenoid cystic carcinoma, epithelial-myoepithelial carcinoma, and mucoepidermoid carcinoma. Though these lesions have similar histological features they differ in their clinical behavior. Adenoid cystic carcinoma, which has significant malignant behavior in the salivary gland, is a silent lesion in the breast. Recently, another entity termed as sclerosing polycystic adenosis has been described in the salivary gland which is histologically similar to a fibrocystic disease, one of the most common benign lesions in the breast.,
SC can present in the age group varying from 13 to 78 years with a mean age of 47 years with slight preponderance in males.,,, Our small series also showed preponderance in males but in the younger age group as compared to other studies. SC is commonly reported to arise from the parotid gland (60% of cases) followed by the submandibular gland (30%), and minor salivary glands in the oral cavity (09%)., The duration of symptoms varied from 6 months to 8 years which shows the slow-growing behavior of the tumor and this is comparable to the recent study with an average duration of a symptom of 14 months. Cases 3 and 4 had a long-standing disease with an initial course like a benign tumor of the salivary gland but turned aggressive in a few weeks making surgery extensive and leading to postoperative morbidity. Due to this clinical behavior in these cases, on histology, we extensively searched for areas of high-grade transformation in the form of nuclear atypia and pleomorphism, hyperchromasia, and increased mitotic activity. However, these features were not seen. In case 4, the tumor was seen abutting the skin epidermis stretched out. However, there was no infiltration. Beta-catenin expression was characteristically absent in the tumor cells.
The incidence of regional lymph node metastasis has been reported up to 20% in the literature. In another series of 31 patients, only one patient had regional lymph node metastasis; hence, authors concluded that elective neck dissection is not required in a node-negative neck. In our series, none of the patients had regional lymph nodes at presentation. Though we performed an elective neck dissection (case 4) in tumor showing aggressive behavior with multiple recurrences, lymph nodes were negative in histopathology. Aggressive clinical behavior has been reported by many authors in patients with SC., Two of our patients had the local aggressive disease in terms of facial nerve involvement, extra-parotid spread, and skin involvement. These patients also had the disease for a long duration of 2 years and 8 years along with recurrences. The 5 years and 10-year disease-free survival and overall survival were reported to be 89% and 95%, respectively. Our median follow-up of 34 months, showed no locoregional recurrence or distant metastasis. Postoperative radiotherapy is required for close or involved resected margins. However, in our small series, one patient (case 4) received adjuvant radiotherapy given skin infiltration and multiple recurrences.
Grossly, SC is well-circumscribed, rubbery in consistency, greyish white to tan in color.,, The cut surface may reveal cystic areas filled with yellowish-white secretions and infiltration into the adjoining salivary gland tissue., Microscopically, the tumor is seen as lobules separated by fibrous septae and the tumor cells may be arranged in solid sheets, forming macro or microcysts, tubules, or micropapillary architecture.,, In case 1 and 2, the lymphocytic infiltrate seen in the septa were very focal and not as characteristically described in acinic cell carcinoma. The septal lymphocytic infiltration is diffuse and moderate to severe in acinic cell carcinoma. The cysts and tubules are filled with bubbly eosinophilic secretions that get stained with mucicarmine, Alcian blue, and PAS reagent and resistant to digestion by diastase.,,,, Cells have vesicular nuclei, finely granular chromatin, centrally located nucleoli and pale, eosinophilic, granular or vacuolated cytoplasm.,, Zymogen granules are not seen in the cytoplasm which helps in differentiating it from one of its close differential, acinic cell carcinoma.,
We have diagnosed four cases of SC based on characteristic morphology and IHC markers. The panel selected while performing the routine diagnostic workup was CK7, vimentin, S100, GCDFP15, P40, and later DOG1 was added to that. PAS with and without diastase and Alcian blue-PAS stain were used as a special stain. Given newly identified pathology, all the four cases were independently re-reviewed by three senior pathologists, and the consensus was reached to diagnose them as SC of salivary glands origin. Characteristic morphology in conjunction with IHC staining is adequate for an accurate diagnosis.,,
The major differential diagnosis of SC is acinic cell carcinoma, polymorphous adenocarcinoma (PAC), low-grade mucoepidermoid carcinoma (LGMEC), and low-grade salivary duct carcinoma., It can be differentiated from ACC by lack of PAS-positive diastase resistant zymogen granules which on H and E stain show amphophilic cytoplasm. Though zymogen poor ACC has an overlapping cytomorphology, SC can be distinguished by more uniform and homogenous cytology and architecture while ACC has variable cytological and architectural patterns., Besides, immunopositivity for vimentin, strong nuclear, and cytoplasmic positivity for S100 and demonstration of ETV6-NTRK3 are the diagnostic features seen in SC which are absent in ACC. The incidence of origin from minor salivary gland tissue is higher with SC than ACC.,,, Thus any extra-parotid salivary gland tumor with zymogen poor cells and characteristic morphology, diagnosis of SC should be considered especially, in conjunction with diffuse and strong S100 positivity.,
Based on a predilection for the oral cavity, PAC is considered as a differential diagnosis. Instead of circumscribed and lobulated appearance in SC, PAC is characterized by infiltrative growth pattern. Though PAC also shows co-expression of S100 and mammaglobin, the number of secretions and cytoplasmic vacuolation is more in SC compared to PAC. Another differential that needs exclusion is low-grade cribriform cystadenocarcinoma (LGCC) on account of similar architecture. LGCC also shows strong and diffuse positivity for S100. However, a complete and intact basal cell layer around the tumor nests in LGCC is missing or if present is not extensive in SC.,, LGMEC can mimic SC due to mucin-producing cells, this was excluded due to lack of Alcian blue-PAS positive mucinous material and lack of P40 immunostain. The pavement like arrangement of squamous cells, intense positivity for HMWCK and P63 in LGMEC are the distinguishing features. Besides, it lacks diffuse and strong S100 positivity and ETV6-NTRK3. Instead 50% of MEC show t(11; 19) translocation coding for a CRTC1-MAML2 fusion protein.
Based on the available literature, we consider that careful observation of morphology in conjunction with characteristic staining pattern precludes the demonstration of ETV6-NTRK3 translocation. Besides, two useful IHC markers adipophilin and mammaglobin help in differentiating SC from other salivary gland malignancies.,, Whereas mammaglobin is occasionally, only focally positive, similar to that seen in acinic cell carcinoma, adipophilin is most specific and not seen in any other salivary gland malignancy.,
| » Conclusion|| |
SC of salivary glands is seen in patients with a wide age range and has a predilection among men. Younger age at presentation and longer duration of presentation are associated with locally aggressive disease. It has distinct histological and IHC features apart from characteristic genetic translocation and fusion. Surgery is the main modality of treatment with or without radiotherapy. Long-term follow-up is required to detect loco-regional and distant metastasis. It shows characteristic ETV6-NTRK3 fusion which may be considered as a potential therapeutic target in the future. Larger case series with longer follow-up is desirable to uncover the biological behavior of this recently recognized pathological entity.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]